It is by now well-documented that peptides such as hormones and cytokines are playing a diversity of critical roles in the body for the maintenance of life. Meanwhile, recent advances in synthetic technology and genetic engineering have enabled the industry to produce, in the pure form and in large quantities, such natural peptides or proteins and even their analogs having modified amino acid sequences and some of them are expected to be of use as medicines.
However, it is known that such physiologically active peptides or proteins generally are decomposed by digestive juices in the gastrointestinal canal or hydrolyzed by the enzymes on the digestive tract wall. It is also known that these substances are poorly absorbed after administration. Therefore, from the expectation to obtain sufficient pharmacological efficacy, these physiologically active peptides or proteins are commonly administered by parenteral injection instead of being administered orally.
However, this route of administration is not only liable to cause pain in the patient but is burdensome to the patient because it does not provide for the choice of self-administration and these disadvantages are particularly noticed when long-term repeated administration is required.
Recently, as an expedient method for administering such a physiologically active peptide or protein, a transmucosal drug delivery system insuring absorption of the peptide or the like from the nasal mucosa, digestive tract mucosa or vaginal mucosa has been proposed. According to this system, based on the rationale that a peptide or protein of high molecular weight, such as calcitonin, insulin or PTH, is hardly absorbed when administered alone, an absorption promoter is generally employed. As pharmaceutical preparations of this kind, the following are known.
Japanese Patent Application (hereinafter referred 10 to briefly as JP) Laid Open No. 58-189118/1983 discloses a technology about a transnasal therapeutic preparation containing a physiologically active polypeptide and, as a transmucosal absorption promoter, a cyclodextrin compound.
JP [Laid Open] No. 59-89619/1984 and [Laid Open] No. 59-130820/1984 disclose the use of an amphoteric, ionic, e.g. cationic, or nonionic surfactant and teach that, among such surfactants, ether-form surfactants, such as polyoxyethylene lauryl ether, which are nonionic, are particularly high in the absorption promoting effect. However, ether-form surfactants implement the penetration of the drug only by impairing the nasal mucosa and because of this tissue-damaging potential, the clinical use of these surfactants cannot be straightforwardly recommended.
JP [Laid Open] No. 59-89619/1984, [Laid Open] No. 59-130820/1984, [Laid Open] No. 61-194034/1986, [Laid Open] No. 64-50823/1989, [Laid Open] No. 1-501550/1989 and [Laid Open] No. 2-503915/1990 disclose technologies about pharmaceutical compositions for administration into the nasal cavity which comprise a surfactant such as benzalkonium chloride, a bile acid salt or a phospholipid as an absorption promoter but since mucosal irritating effects are unavoidable, they can hardly be administered repeatedly for a long time.
JP [Laid Open] No. 61-118325/1986 discloses a calcitonin transnasal therapeutic composition containing a basic and/or neutral amino acid as the absorption promoter, JP [Laid Open] 61-126034/1986 discloses a similar composition containing aldose, JP [Laid Open] 61-267528/1986 discloses a composition containing polyethylene glycol 400, and JP [Laid Open] 63-39822/1988 discloses a composition containing a sucrose fatty acid ester. However, many of these absorption promoters are toxic to the mucosa.
JP [Laid Open]1-501550/1989 discloses a transnasal therapeutic composition containing a polypeptide such as insulin and, as the absorption promoter, a phospholipid or a derivative thereof, such as a phosphatidylcholine, a phosphatidylethanolamine and so on. JP [Laid Open] 2-503915 discloses a technology employing a lysolecithin, lysophosphatidylethanolamine, lysophosphatidic acid or the like as a surfactant component. Although these substances are physiological substances and, as such, are metabolized in the body, they are surfactants of a sort and may have irritation potentials (Suzan, Chandler, et al., International Journal of Pharmaceutics, 76, pp. 61-70, 1991).